B cells regulate atherosclerosis with adaptive B-2 cells aggravating atherosclerosis and innate B-1 cells attenuating atherosclerosis. B-1 cell production of IgM to oxidation specific epitopes (OSE) on LDL such as MDA-LDL is thought to occur in the bone marrow and spleen and serve to block the inflammatory effects of these modified lipids. However, we and others demonstrated that atheroprotective B-1 cells reside in the outer layer of the vessel wall including perivascular adipose tissue (PVAT), a region known to play an important role in vascular inflammation and atherosclerosis. Preliminary data provide the first evidence for B-1 cell derived IgM production in the PVAT of mice and demonstrates that adipose tissue B-1-derived IgM limits M1 macrophage production of inflammatory cytokines, a potential mechanism whereby PVAT IgM may attenuate atherosclerosis. Preliminary murine data implicates the chemokine receptors (CR) CCR6 and CXCR4 in B-1 cell-mediated IgM production in PVAT and atheroprotection. Consistent with murine findings, we identified B-1 cells and IgM production in coronary artery PVAT of humans. Moreover, utilizing our well phenotyped human cohort at UVA, preliminary data suggests that CXCR4 expression on circulating human B-1 cells positively associates with plasma levels of IgM to MDA-LDL and inversely associates with human coronary artery plaque volume and indices of plaque instability as measured by intravascular ultrasound-virtual histology (IVUS- VH). Accordingly, we hypothesize that specific CR expression on B-1 cells leads to increased numbers of B-1 cells in PVAT and these B-1 cells inhibit inflammatory cytokine production by M1 macrophages and attenuate diet-induced atherosclerosis in an IgM- dependent manner. We further hypothesize that expression of specific CRs on human B- 1 cells is positively associated with plasma IgM to OSE and is inversely associated with coronary artery plaque volume and indices of plaque instability. To test this hypothesis, we propose the following aims: Specific Aim 1: Test the hypothesis that the expression of specific CRs (CXCR4, CCR6 and CXCR5) on B-1 cells promotes their recruitment to the PVAT and enhances local IgM production. Specific Aim 2: Test the hypothesis that CR-mediated B-1 production of IgM in PVAT reduces PVAT and lesional inflammation and diet-induced atherosclerosis. Specific Aim 3: Identify CRs on human circulating CD20+CD27+CD43+ B cells that are inversely associated with plaque burden and plaque instability in humans as measured by IVUS-VH and determine if these unique B-1 subsets spontaneously produce IgM to OSE and are associated with plasma levels.